The striatum is mostly comprised of GABAergic medium spiny projection neurons (MSNs) that differ in their neuropeptide expression and form two major efferent pathways. MSNs that contain the neuropeptides dynorphin and substance P are part of the striatonigral, or 'direct', pathway whereas MSNs that contain the neuropeptide enkephalin are part of the striatopallidal, or 'indirect', pathway. Psychostimulant-induced alterations in the striatum are thought to be critical in the development and maintenance of drug addiction;however, the role of specific striatal cell populations is not clear. Nonetheless, recent evidence suggests that striatopallidal neurons may be especially important for the long-term changes in brain and behavior produced by drugs. For example, studies using immediate early gene expression as an indicator of neuronalactivity found that while mere psychostimulant exposure is sufficient to increase activity in striatonigral neurons, only drug exposure under conditions that lead to forms of drug-induced behavioral plasticity, such as psychomotor sensitization, also activates striatopallidal neurons. The overall aim of the proposed experiments is to use novel molecular and genetic targeting approaches to directly examine the involvement of striatopallidal MSNs in drug-induced molecular changes and behavioral plasticity. It is hypothesized that recruitment of striatopallidal neurons is critical for the long-term changes in striatal gene expression induced by psychostimulants, as well as in the development of psychomotor sensitization and the escalation of drug self-administration behavior. This work will help to elucidate the contribution of striatopallidal medium spiny neurons in the processes that underlie addiction. In addition, precise identification of the neural circuits that regulate the transition to addiction should be useful for guiding the development of future treatments for addicts. PUBLIC HEALTH RELEVANCE: Drug addiction has become a worldwide epidemic with major social and economic burdens on society. The research that comprises this proposal aims to better understand how brain regions, and specific cells within those regions, contribute to the development of addiction. In so doing, this research may provide avenues for novel lines of therapeutic interventions in order to mitigate this serious public health issue.